Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection

Abstract

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for, but on average only 53% did for and 3% for, at the 15-mg/kg oral dose. For treating urinary tract infections caused by , oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).

Physiologically-Based Pharmacokinetic model for Ciprofloxacin in children with complicated Urinary Tract Infection

“…Recently, Meesters et al [11] have developed a population pharmacokinetic model of ciprofloxacin in children with cUTI finding that V d and total plasma CL were 83.6% and 41.5% reduced, respectively, with respect to healthy children and paediatric patients with CF [9,10]. These findings are in accordance with previous observations, indicating that renal impairment affects drug disposition beyond the impact on renal clearance [12].…”

“…In the current analysis, the PBPK approach has been used to mechanistically describe the systemic and urinary ciprofloxacin exposure in children suffering from cUTI, a disease causing serious alterations in processes involved in its PK. In fact, a recent pharmacokinetic study of ciprofloxacin administered to cUTI children showed that the apparent V d and the total plasma CL were decreased compared to healthy children (up to a 83.6% and 41.5%, respectively), presenting a degree of inter-individual variability not explained by any of the patient's factors ranging from 60 to 160% [11]. The lack of literature examples extrapolating from healthy subjects to the patient population, thus beyond ontogeny, and towards the population of interest, exemplify the novel contribution of the current work within the extensive literature on both PBPK and ciprofloxacin [9,14,[16][17][18][19][20][21]36].…”

“…Model adaptation of GFR, TS_CL int and CL CYP1A2 according to KF partially explained the differences seen in the plasma drug concentrations and f e vs. time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI due to the known large heterogeneity in patients suffering from CAKUT [11]. This study provides not only an evaluated PBPK model of ciprofloxacin for healthy children, but also essential key parameters to suggest hypotheses for further fine-tuning of the PBPK model in a cUTI population.…”

Antibiotics and its altered pharmacokinetics in the pediatric population : An evidence-based review

“…The clearance of cipro loxacin is signi icantly lower in new-borns than the other children; however, a wide interindividual variability exists within each age group (Meesters et al, 2018). The postnatal age, current body weight, renal function indicated by serum creatinine concentrations has a signi icant effect on the clearance of cipro loxacin in children.…”

“…The association of renal function and cipro loxacin clearance is explained by the difference in renal physiological and anatomical maturation since cipro loxacin is primarily excreted by the kidneys. Cipro loxacin clearance is increased allometrically with current weight in neonates and young infants and illustrates the independent impact of both gestational and postnatal ages on antenatal and postnatal renal maturation.Fat-free mass and glomerular iltration rate standardized for body surface area may also act as considerable covariates for cipro loxacin clearance in children (Meesters et al, 2018;Payen et al, 2003;Zhao et al, 2014) The clearance of cipro loxacin in children and adults was found to be 29.9 L/hr and 31.9 L/hr with a child to adult ratio of 0.94 whereas V d was found to be 260 and 154L/kg (child: adult-1.69), respectively (Holford et al, 2013). However, more pharmacokinetics studies are required to design an optimum dosage regimen for cipro loxacin in the pediatric population.…”